Progressive cognitive and physical function decline in the aging population in the United States requires a substantial allocation of healthcare resources. Aging is also associated with increased prevalence of chronic kidney disease. Advanced kidney failure is an important etiology of cognitive and physical dysfunction, likely mediated through vascular disease, abnormal mineral metabolism, and neuromuscular degeneration, but sparse data are available concerning the role of mild and moderate kidney failure. We hypothesize that mild and moderate chronic kidney disease will be independently associated with cognitive and physical decline in older adults. This prospective study will include 3700 community-dwelling women participating in the Nurses' Health Study who are aged 70 and older, have stored plasma from 1989 and 2000, stored urine from 2000, and who have undergone repeated cognitive function testing every two years. Physical function is assessed every four years by the physical component score of the Short Form-36, walking pace, and frequency of falls as reported on the questionnaires. Our measurements of cognitive and physical functioning have been validated as significant predictors of morbidity and mortality in population-based studies of older adults. We will assay plasma for creatinine, which will allow us to estimate GFR, and urine for microalbuminuria. A growth curve approach to multivariable modeling to test for associations between kidney dysfunction and subsequent 1) cognitive or 2) physical function decline will allow us to take advantage of multiple repeated measures of these outcomes obtained between 2000 and 2008. Specific aims of this proposal include evaluating how 1) baseline eGFR in 2000, 2) >25% eGFR decline between 1989 and 2000 (over 11 years), and 3) presence of microalbuminuria are related to cognitive and physical decline between 2000 and 2008 (over 8 years). We will also investigate whether inflammatory biomarkers, namely C- reactive protein, fibrinogen, and tumor necrosis factor a receptor-2, may potentially mediate associations between kidney dysfunction and functional decline. We will have >80% power for our aims. Completed and on-going work in this established cohort make this project extremely cost-effective. From a public health perspective, recognition of these associations may result in improving clinical care for the geriatric population through medical management strategies that slow progression of early and moderate kidney disease, cognitive impairment, and physical function decline. Thus, findings from this longitudinal, prospective study of a large cohort of older women will meaningfully improve the quality of life and longevity of community-dwelling older citizens. [unreadable] [unreadable] [unreadable] [unreadable]